tbuckley/cabot-search huggingface dataset:
Randomized, phase II selection study of ramucirumab and paclitaxel versus FOLFIRI in refractory small bowel adenocarcinoma: SWOG S1922.
Authors: Michael J. Overman, Katherine A Guthrie, Mohamed E. Salem, Katrina Sophia Pedersen, Aparna Kalyan, Sarah Colby, Marwan Fakih, Sepideh Gholami, Philip Jordan Gold, E. Gabriela Chiorean, Howard S. Hochster, Philip Agop Philip
Journal: Journal of Clinical Oncology (2023)

TPS784 Background: Small bowel adenocarcinoma is a rare malignancy with limited evidence to support the choice of systemic chemotherapy beyond the frontline setting. Though second-line therapy has historically been extrapolated from colorectal cancers, recent molecular data has demonstrated small bowel adenocarcinoma to be genomically unique when compared to either colon or gastric cancer. Retrospective analyses of irinotecan- and taxane-based therapies and one prospective phase II clinical trial of nab-paclitaxel have demonstrated clinical activity in this cancer. Ramucirumab/paclitaxel represents an active combination in the management of gastric cancer. SWOG 1922 evaluates the use of FOLFIRI or ramucirumab/paclitaxel in the second- and later-line setting for small bowel adenocarcinoma. Methods: This is randomized, phase II, selection design clinical trial of FOLFIRI (5-fluorouracil, leucovorin and irinotecan) every two weeks or ramucirumab D1,15 and paclitaxel D1,8,15 every 4 weeks with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response rate, overall survival, and safety. Archived paraffin tumor tissue collection and serial blood collections are included for correlative analyses. Key eligibility criteria include having mismatch repair proficient/microsatellite stable small bowel adenocarcinoma (ampullary location excluded); metastatic or locally advanced unresectable disease; prior fluoropyrimidine and/or oxaliplatin therapy; no prior treatment with irinotecan, ramucirumab, or taxanes; no recent bleeding, blood clots, or bowel perforation/fistula; and Zubrod performance status of 0/1. Measurable disease is not required. The null hypothesis is median PFS of 2.5 months. If a median PFS of at least 3.5 months is observed in one or both arms, the goal is to choose the better regimen with respect to this endpoint. The design provides a 90% probability of selecting the more active arm, assuming a hazard ratio of 1.4, if both arms meet this threshold. This trial is open and, as of September 1, 2021, 21 of 94 planned patients have been enrolled. NCT04205968 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by Eli Lilly and Company. Clinical trial information: NCT04205968 .
Phase I study of trifluridine/tipiracil in combination with gemcitabine (gem) and nab-paclitaxel (nab-P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Anita Ahmed Turk, Paul R. Helft, Amikar Sehdev, Safi Shahda, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2023)

731 Background: The incidence of PDAC is on the rise and it is predicted to be the 2nd leading cause of cancer related mortality in the next decade. Most patients present with advanced disease at diagnoses with limited systemic treatment options. Fluoropyrimidines are active in PDAC. Lonsurf (L) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Preclinical data demonstrate Lonsurf may have activity in 5-FU resistant malignancies. This phase I study combines Gem, nab-P, and L. Methods: Gem and nab-P are dosed on days 1 and 15 IV on a 28 day cycle. L (20-30mg/m2) is dosed twice daily on days 2-6 and 16-20 (table 1). Dose escalation is by 3+3 design. Key eligibility include pts with untreated locally advanced or metastatic PDAC, ECOG 0-1, and adequate hepatic and bone marrow function. Results: 14 pts (median age 62 yrs [range 43-74]) have been enrolled. Dose was initiated at DL1. The first 3 pts were treated without DLT. DL2 exceeded the MTD with 1 patient experiencing grade 3 infection (cholangitis). Dose expansion to 7 patients was completed at DL 1 with no further DLTs. The RP2D is Gem 800mg/m 2 , Nab-P 100mg/m 2 , and L 25mg/m 2 . Of the 10 patients with evaluable disease, 2 (20%) had PR and 7 (70%) had SD. Pts were on study a median of 14 months (range 4 -31+). Most common grade 3/4 AEs include fatigue (46%,) neutropenia (38%), anemia (31%) anorexia (15%), nausea (15%), vomiting (15%), abdominal pain (15%), hyperglycemia (15%). No grade 5 events occurred. Conclusions: The RP2D is Gem 800mg/m 2 , Nab-P 100mg/m 2 , and L 25mg/m 2 . This combination was well tolerated with expected toxicities of myelosuppression with prolonged responses seen. Clinical trial information: NCT04046887 . [Table: see text]
Updated results of a phase 1 study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC; SGNS40-001).
Authors: Andrew L. Coveler, Martin Gutierrez, Gina M. Vaccaro, Ursa Brown-Glaberman, Juneko E. Grilley-Olson, Hedy L. Kindler, Mark Zalupski, Elisabeth I. Heath, Sarina A. Piha-Paul, Allison Wehr, Hailing Lu, Jonathan Hayman, David L Bajor
Journal: Journal of Clinical Oncology (2023)

708 Background: PDAC has a 5-year survival rate of &lt;5% in patients with metastatic disease. Despite established frontline therapy with gemcitabine + nab-paclitaxel (GnP), outcomes remain poor and additional therapies are urgently needed. SEA-CD40 is a receptor-agonistic, nonfucosylated IgG1 antibody directed to CD40. SEA-CD40 binding to FcγRIIIa results in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. In preliminary results of a phase 1 study, SEA-CD40 + GnP + pembrolizumab (pembro) showed a tolerable safety profile and evidence of immune activation in patients (pts) with PDAC. Here, we present updated clinical results for this cohort. Methods: Pts were ≥18 years old with untreated metastatic PDAC and ECOG Performance Status of 0 or 1. Gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) were given on days 1, 8, and 15 and SEA-CD40 (10 or 30 µg/kg) was given on day 3 of each 28-day cycle. Pembro (400 mg) was given every 6 weeks starting on day 8 for up to 2 years. Results: As of August 16, 2022, 61 pts were treated with 10 µg/kg (N=40) or 30 µg/kg (N=21) SEA-CD40. Median duration of exposure was 25.1 weeks. Confirmed objective responses were observed in 19 pts (48% [95% CI 31.5, 63.9]) at 10 µg/kg and 8 pts (38% [95% CI 18.1, 61.6]) at 30 µg/kg. Median duration of response (months) was 5.7 (95% CI 3.9, 7.4) and 5.7 (95% CI 2.3, 9.2) for the 10 and 30 µg/kg dose groups, respectively. Additional efficacy results are summarized. The most common treatment-emergent adverse events (TEAEs) across dose groups were fatigue (84%), nausea (74%), and neutropenia (67%). The most common grade ≥3 TEAEs across the groups were neutropenia (61%), anemia (33%), and thrombocytopenia (20%). TEAEs leading to treatment discontinuation were reported in 10% of pts, including immune-mediated lung disease (n=3) and septic shock (n=1) in the 10 µg/kg dose group, and colitis (n=1) and portal vein thrombosis (n=1) in the 30 µg/kg dose group. Conclusions: The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699 . [Table: see text]
A phase I study of a mutant KRAS-targeted long peptide vaccine in patients at high risk of developing pancreatic cancer.
Authors: Saurav Daniel Haldar, Carol Judkins, Anna Ferguson, Elizabeth Abou Diwan, Su Jin Lim, Hao Wang, Julie Nauroth, Michael Goggins, Dan Laheru, Elizabeth M. Jaffee, Nilofer Saba Azad, Neeha Zaidi
Journal: Journal of Clinical Oncology (2023)

TPS758 Background: KRAS mutations are identified in the majority of premalignant lesions that precede pancreatic ductal adenocarcinoma (PDAC). Arising during tumorigenesis, mutant KRAS (mKRAS) neoantigens are less susceptible to central tolerance mechanisms and serve as ideal vaccine targets. Indeed, targeting mKRAS neoantigens with vaccines has shown promising anti-tumor activity in the preclinical setting. For instance, our group previously demonstrated that a Listeria-based vaccine targeting mKRAS G12D combined with Treg-depleting agents can prevent the progression of early pancreatic intraepithelial neoplasia to overt PDAC in a mouse model (Keenan et al, 2014). Building upon this work, the current study aims to determine the safety and immunogenicity of a pooled synthetic long peptide (SLP) mKRAS vaccine in patients identified as high risk for developing PDAC based on family history and germline mutation testing. Methods: This is a single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine in patients at high risk of developing PDAC ( n = 20). The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. A four-dose series of the mKRAS vaccine is administered on weeks 1, 3, 4, and 17. Following completion of the treatment phase, all patients have the option to continue annual follow-up visits until study closure. Eligible patients must have radiographic evidence of a premalignant pancreatic lesion and fall under at least one of the following three high-risk groups: 1) ≥ 2 familial pancreatic cancer relatives, 2) germline mutation carriers with ≥ 10% lifetime PDAC risk and 3) germline mutation carriers with ~5% lifetime PDAC risk. The co-primary endpoints of this study are safety and T cell response. Safety will be assessed by the frequency and grading of adverse events per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Correlative studies will explore vaccine-associated changes in T cell quality (e.g., memory, exhaustion, poly-functionality, and activation) using mass cytometry analysis of peripheral blood samples. Patient accrual began in April 2022 and is currently ongoing. Clinical trial information: NCT05013216 .
Ex vivo oncolytic and immune activity of CF33-hNIS-antiPDL1 against fresh peritoneal cells from patients with gastric cancer with and without peritoneal metastases.
Authors: Zhifang Zhang, Annie Yang, Shyambabu Chaurasiya, Anthony K Park, Sang-In Kim, Jianming Lu, Hannah Valencia, Yuman Fong, Yanghee Woo
Journal: Journal of Clinical Oncology (2023)

430 Background: No effective therapy exists for peritoneal metastases (PM) from gastric cancer (GC), which remain fatal within months of diagnosis. We investigated a novel chimeric oncolytic virus platform, CF33-OV, for its anti-cancer potential against peritoneal cancer cells from GC patients. Methods: We prospectively collected fresh ascites or peritoneal washings from 30 GC patients between 2019 and 2020. These included 16 males (53.3%) and 14 females (46.7%) with a mean age of 51.3 ± 15.1 years. Of the 30 patients, 23 (90%) had cytology or biopsy-proven PM. Cells isolated from the peritoneal fluid were analyzed using flow cytometry for immune cell markers and/or treated with PBS, CF33-GFP (MOI=3), or CF33-hNIS-antiPDL1 (MOI=3) for 15 hours. We evaluated the treated cells for virus infection, replication, CD8 + and CD4 + expression with exhaustion markers, virus infection, replication, and cytotoxicity. We evaluated ex vivo CD274 (PD-L1) blockade by virus-encoded anti-PD-L1 scFv and the release of growth factors and cytokines following CF33-hNIS-antiPDL1 treatment. Results: The CD45- cancer cell percentage was higher, and the CD8+ T cell percentage was significantly lower in the ascites group than in the peritoneal washing group. At baseline, low levels of CD274 (PD-L1), CD252 (OX40L), and EGFR were identified on the surface of cancer cells. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. After 15 hours of treatment, CF33-GFP infected, replicated in, and killed cancer cells ex vivo with a significantly higher dead cell percentage than the PBS control group (10.8% treated vs. 3.1% control, p-value &lt;0.05). Of the live cancer cells, 69% were GFP+ by flow cytometry. Fluorescence microscopy results confirmed virus-encoded GFP expression in the ex vivo cells. Moreover, CF33-hNIS-antiPDL1 produced functional anti-PD-L1 scFv, which blocked phycoerythrin labeled anti-PD-L1 binding to PD-L1 on live cancer cells. Virus treatment increased CD8 + CD107α + and CD4 + CD107α + T cell percentages while decreasing the release of growth factors (EGF and PDGF) and inhibitory immune factors (soluble anti-PD-L1, GM-CSF, and IL-10). Conclusions: CF33-hNIS-antiPDL1 is oncolytic with immune-activating effects against GCPM ex vivo and has solid potential for intraperitoneal therapy of GCPM patients.
Risk of gastric cancer development according to the combination of anti–Helicobacter pylori antibody titer and degree of atrophic gastritis.
Authors: Joo Hyun Lim, Soo Jeong Cho
Journal: Journal of Clinical Oncology (2023)

297 Background: Helicobacter pylori is known as the main risk factor for gastric cancer. It is also well known that gastric atrophy which is the result of long-term H. pylori infection induces spontaneous regression of H. pylori infection and such atrophic status with negative H. pylori infection is related with high risk of gastric cancer, as in so called “ABC method”. However the implication of anti- H. pylori antibody titer is not well investigated. This study was designed to identify the risk for gastric cancer according to the combination of level of anti- H. pylori antibody titer and gastric atrophy. Methods: Those who had health checkups including upper endoscopy and serum anti- H. pylori antibody test between 2003 and 2018 were enrolled. Among them, those who had positive results for anti- H. pylori antibody were included in this study and those who had followed up for less than 1 year were excluded. Kimura-Takemoto classification C3 or more was defined as gastric atrophy. Individuals were classified into 4 groups: low B (low titer without atrophy), high B (high titer without atrophy), high C (high titer with atrophy), and low C (low titer with atrophy). Their risks for gastric cancer were compared under adjustment with other risk factors. Results: During median 5.7 years of follow-up, among 28,311 subjects, 231 developed new gastric cancer. Among them, 159 were intestinal type, 68 were diffuse type, and 4 were type-unknown. For intestinal type gastric cancer, high C group and low C group showed significantly high risk compared with low B group (high C: aHR 10.516; 95% CI, 6.485-17.054) (low C: aHR 11.191; 95% CI, 7.096-17.649). However, for diffuse type gastric cancer, high B group showed higher risk compared with low B group (aHR, 1.713; 95% CI, 1.021-2.875). When those two factors were taken separately, grade of atrophy was related with the risk for intestinal type gastric cancer (aHR, 2.047; 95% CI, 1.862-2.251), while the level of anti- H. pylori antibody titer was related with the risk for diffuse type gastric cancer (aHR, 1.158; 95% CI, 1.041-1.288). Conclusions: Among those with current H. pylori infection, high anti- H. pylori antibody titer is related with diffuse type gastric cancer. The risk was prominent especially among those without atrophy. Therefore, those with high level of anti- H. pylori antibody titer need to be considered as high risk group even without atrophy and should be considered as good candidates for H. pylori eradication and intensive screening.
Clinicopathological features of HER2-low expressed advanced gastric cancers.
Authors: Izuma Nakayama, Daisuke Takahari, Keisho Chin, Takeru Wakatsuki, Akira Ooki, Mariko Ogura, Koshiro Fukuda, Hiroki Osumi, Shota Fukuoka, Eiji Shinozaki, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2023)

459 Background: The DESTINY-Breast04 data demonstrated the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also effective for metastatic breast patients (pts) with HER2-low expression. Now that the HER2-low expressed cancer is categorized as an independent subset in breast cancer patients. It is unknown whether patients with the HER2-low expression are distinguishable from the HER2 negative or positive and are potential candidates for the anti-HER2 therapy in advanced gastric cancer (AGC) patients. Methods: We retrospectively reviewed the medical records of AGC pts who received standard chemotherapy with platinum containing regimens as the first-line treatment between Jan, 2011 and Dec, 2018 at the Cancer Institute Hospital of the JFCR. AGC pts were classified according to the HER2 status using immunohistochemistry (IHC) and in situ hybridization (ISH) as follows; HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-) and HER2 positive (IHC2+/ISH+ or 3+). This study was conducted to investigate the clinicopathological features and prognosis of HER2-low AGC pts compared with HER2 negative and positive. Results: A total of 734 AGC pts were received HER2 testing and classified into three groups according to HER2 status (HER2 negative; n=410, HER2-low; n=154, HER2 positive; n=170). The proportion of male (negative; 61.5%, low; 63.6% and positive; 69.4%), intestinal histology (negative; 21.0%, low; 44.2% and positive; 59.8%), liver metastases (negative; 18.3%, low; 24.8% and positive; 46.5%), higher serum CEA level (&gt;ULN) (negative; 32.2%, low; 41.6% and positive; 56.5%) and higher serum CA19-9 level (&gt;ULN) (negative; 34.1%, low; 36.7% and positive; 56.5%) were gradually increased along with HER2 expression level. The proportion of peritoneum metastasis (negative; 56.3%, low; 44.8% and positive; 21.8%) was decreased along with the HER2 expression level. One hundred and fifty-two pts (89.4%) received combination chemotherapy with trastuzumab in the first-line treatment. Sixteen pts received trastuzumab in the HER2-low (n=3) and HER2 negative (n=13) in the clinical trial. The median survival time (MST) of pts with HER-low was the same with that of HER2 negative (15.7ms). The statistically significant difference was observed in OS between the HER2-low and HER2 positive (HR 1.43 95% CI: 1.12-1.83, P=0.003). Conclusions: AGC Pts with HER2-low have intermediate clinicopathological features between HER2 negative and positive. A Novel effective anti-HER2 therapy for the HER2-low expressed tumor would be warranted in AGC treatment.
Camrelizumab combined with apatinib and albumin-bound paclitaxel followed by camrelizumab plus apatinib as first-line therapy for unresectable or metastatic pancreatic cancer.
Authors: Bo Shen, Yuan Wu
Journal: Journal of Clinical Oncology (2023)

703 Background: Pancreatic carcinoma has complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Apatinib (small molecular agent targeting the VEGFR-2), has shown the potential additive or synergistic antitumor effects with camrelizumab (anti-PD-1 agent) in vitro study. The inhibition of VEGF signaling pathway could trigger immune suppression provoked. Considering the anti-PD-1 agent plus antiangiogenic drug might avoid the substantial cumulative toxicities and obtain well tolerance, the specific and optimized therapeutic agents and treatment strategy to carry out chemotherapy-free strategy as maintenance or sequential (switch maintenance) therapy is hopeful and noteworthy. Methods: In this single-arm, single-center, exploratory study, patients (pts) who were pathologically or cytologically diagnosed as unresectable or metastatic pancreatic cancer and had not received systemic treatment before, with an ECOG performance status of 0-2. Pts received camrelizumab (200 mg intravenously once every 3 weeks) plus albumin-bound paclitaxel (125 mg/m 2 intravenously on day 1,8 every 3 weeks) and apatinib (250 mg once daily orally on days 1–21 of each 3-week cycle) for 4–6 cycles, and pts without progressive disease (PD) after completing 4–6 cycles of initial camrelizumab plus albumin-bound paclitaxel and apatinib were administrated subsequent camrelizumab (200 mg intravenously once in 3 weeks) plus apatinib (250 mg once daily orally on days 1–21 of each 3-week cycle). Primary endpoint was progressionfree survival (PFS) by RECIST 1.1. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From 09/2021 to 08/2022 13 pts were enrolled (median age 60, 77% male). At data cutoff, 5 pts continued to receive subsequent camrelizumab plus apatinib, 12 pts were included in the efficacy analysis. The ORR was 16.7%, with confirmed 2 (16.7%) PR. SD were 9 (75.0%) with a DCR of 91.7%. All pts experienced treatment-related AEs (TRAEs), the ≥grade 3 TRAEs were GGT increased (31%), blood bilirubin increased (8%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), alkaline phosphatase increased (8%), creatinine increased (8%), hypoesthesia (8%) and malaise (8%). Of 13 patients, 5 (38%) had TRAEs leading to any treatment interruption, and 5 (38%) patients had TRAEs leading to any dose reduction, respectively. None patient died because of TRAEs. Conclusions: Camrelizumab combined with apatinib and albumin-bound paclitaxel followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as firstline therapy for patients with unresectable or metastatic pancreatic cancer. Clinical trial information: ChiCTR2100045844 .
Irreversible electroporation as treatment option within a multidisciplinary approach for locally advanced pancreatic cancer.
Authors: Ansley Beth Ricker, David A Iannitti
Journal: Journal of Clinical Oncology (2023)

727 Background: The treatment plan for patients diagnosed with locally advanced pancreatic cancer (LAPC) is developed by a multidisciplinary team by which systemic chemotherapy is employed followed by surgical resection. Strategies that provide local control in LAPC patients who demonstrate stability/regression without metastasis have gained increasing attention. Irreversible electroporation (IRE) is a non-thermal ablative approach that employs short, high-voltage electrical pulses to create permanent nano-defects in the tumor cell membrane resulting in lethal disruption of tumor cell homeostasis while preserving the integrity of the underlying vascular architecture. This study sought to review IRE outcomes at a high-volume, single institution hepato-pancreato-biliary surgical center. Methods: After obtaining institutional review board approval, data for patients treated with IRE was retrieved from the electronic medical record from 2013-2022. IRE in situ is defined as non-thermal ablation to a tumor without resection. Margin enhancement IRE is defined as non-thermal ablation to residual tumor that could not be resected in its entirety within the adventitial plane. IRE assisted resection is defined as non-thermal ablation to a tumor encasing surrounding structures to allow for complete resection. Results: A total of 101 IREs have been performed at our institution from 2013-2022. Demographics for our cohort include 48 (47.5%) female patients, an average age of 63 years (range 43 – 84), and an average BMI of 26.4 kg/m2 (range 17 – 47). Of these IRE operations, 27 (26.7%) were in-situ, 35 (34.7%) were margin enhancement, and 50 (49.5%) were assisted resections. 2.0% and 11.9% died within 30 and 90 days of the operation, respectively. Median disease-free survival for our patient cohort was 15 months (range 0 to 74). 1-year, 3-year, 5-year, and overall survival for the three cohorts are shown. Conclusions: Using IRE in patients presenting with LAPC provides additional treatment options to the standard treatment pathway. Further classifying IRE use to in situ, margin enhancement, and assisted resection and incorporating these procedures into a multidisciplinary treatment approach has the potential to improve survival rates for appropriately selected LAPC patients. [Table: see text]